This proposal seeks elucidation of the molecular mechanisms and cell lineage relationships underlying transitions of the small cell lung cancer (SCLC) to the non-SCLC phenotype. This transition may be an important component of tumor progression and accompanying treatment resistance in patients with SCLC. The studies focus upon a cell culture model in which complementation events between myc and ras oncogenes induce the transition of SCLC to a form of large cell undifferentiated lung cancer. In this model, we seek to determine the molecular events through which the c- and n-myc genes modulate cellular responses to a mutated ras genes, including interactions between myc proteins and expression of protein kinase C genes. We are also exploring a series of expression changes for genes important to cell growth which accompany, in the culture model, the transition of the SCLC to the large cell phenotype. These include activation of the transforming growth factor alpha (TFG-alpha), epidermal growth factor receptor (EGF-R) and platelet derived growth factor (PDGF) genes. The roles of each of these genes in the transition of the SCLC to the large cell phenotype is under study. Finally, the cell lineage relationships inherent to the transition are being investigated by exploring the potential of the induced large cell phenotype to differentiate towards the other major phenotypes of human lung cancer, SCLC, adeno- and squamous cell carcinomas.